Although not established for certain, an impresive amount of biological evidence supports the hypothesis that the critical cellular target for carcinogenesis is DNA. With this as a working hypothesis, therefore, we have investigated the interaction of carcinogens with DNA of human fibroblasts in culture and analyzed the effect of DNA repair on this interction. Diploid human cells offer a unique advantage for such studies because of their high rates of excision repair an d because of the availability of repair deficient XP stains. We have demonstrated that if repair proficient human cells are prevented from replicating by being grown to confluence, but allowed time to excise, they can eliminate potentially lethal and mutagenic effects of exposure to carcinogens. We have developed quantitative mehods to measure the rate o repair replicatin as well as the removal of specific carcinogen residues covalently bound to DNA. Our studies indicate that the rate of excision repair is critical for determining the ultimate cytotoxic effect of carcinogens and that is critical because the numberof unexcised lesions remaining in DNA at the time semiconservative DNA replication takes place ultimately determines the mutagenic effect of the damage. Because genetically altered cell characteristics may be responsible for the initiation of malignant transformation, we propose to investigate: 1. the kinetics of excision repair induced by different chemical cacinogens, the number and kind of adducts removed, the nature of the excised region, and whether these adducts cause significant distortion of the DNA. in order to correlate these with the biological connequences of carcinogen treatment; 2. the critical relationship between the rate of excision repair, the length of cell cycle, and the biological effects o exposure to carcinogens; 3. the postreplication repair mechanisms used by human cells to cope with unexcised damage; 4. whether the presence of RNA tumor viruses alters the cells' repair capabilities; and 5. whether the carcinogenic potency of a series of structurally-related polycyclic hydrocarbons is correlated with differences in rates of metabolism, rates of binding to DNA, rates of excision repair, or intrinsic mutagenic potency of particular DNA adducts.